rs773670891
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_020451.3(SELENON):c.402_403+2delGAGT(p.Arg135fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 274,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L134L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_020451.3 frameshift, splice_donor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.402_403+2delGAGT | p.Arg135fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | Exon 3 of 13 | ENST00000361547.7 | NP_065184.2 | |
SELENON | NM_206926.2 | c.301+956_301+959delGAGT | intron_variant | Intron 2 of 11 | NP_996809.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.401_403+1delTGAG | p.Leu134del | splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant | Exon 3 of 13 | 1 | NM_020451.3 | ENSP00000355141.2 | ||
SELENON | ENST00000374315.1 | c.301+955_301+958delTGAG | intron_variant | Intron 2 of 11 | 5 | ENSP00000363434.1 | ||||
SELENON | ENST00000354177.9 | c.301+955_301+958delTGAG | intron_variant | Intron 2 of 11 | 5 | ENSP00000346109.5 | ||||
SELENON | ENST00000494537.2 | n.301+955_301+958delTGAG | intron_variant | Intron 2 of 12 | 3 | ENSP00000508308.1 |
Frequencies
GnomAD3 genomes AF: 0.000303 AC: 46AN: 152012Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 4AN: 35924Hom.: 0 AF XY: 0.0000501 AC XY: 1AN XY: 19970
GnomAD4 exome AF: 0.0000655 AC: 8AN: 122162Hom.: 0 AF XY: 0.0000282 AC XY: 2AN XY: 70868
GnomAD4 genome AF: 0.000302 AC: 46AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74368
ClinVar
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 19, 2024 | Variant summary: SELENON c.402_403+2delGAGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of SELENON function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 274290 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SELENON causing Eichsfeld Type Congenital Muscular Dystrophy (0.0002 vs 0.0011), allowing no conclusion about variant significance. c.402_403+2delGAGT has been reported in the literature in the heterozygous state in a sudden death of a young individual (Salfati_2019). This report does not provide unequivocal conclusions about association of the variant with Eichsfeld Type Congenital Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 461633). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 31, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 15, 2024 | This variant results in the deletion of part of exon 3 (c.402_403+2del) of the SELENON gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is present in population databases (rs773670891, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of SELENON-related conditions (PMID: 31847883). ClinVar contains an entry for this variant (Variation ID: 461633). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The c.402_403+2del variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.1% (13/9840) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773670891). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 461633) and has been interpreted as likely pathogenic by Invitae, GeneDx, and PerkinElmer Genomics. Conservation and expression data indicate that this exon might not be biologically relevant for this disease, and therefore this variant is not expected to result in loss of function of SELENON. In summary, the clinical significance of the c.402_403+2del variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 12, 2021 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21131290, 21670436) - |
Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 04, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at